The Candidate: Alan R. Shuldiner received his MD degree from Harvard Medical School in 1984. We was a resident in internal medicine at Columbia-Presbyterian Hospital and a postdoctoral fellow in Endocrinology at NIDDK, NIH. Dr. Shuldiner is professor and Head Division of Diabetes, Obesity and Nutrition. His major research interest is in the clinical pathophysiology and genetics of type 2 diabetes, insulin resistance and obesity. This K24 award will ensure that Dr. Shuldiner devotes at least 30% of his effort to patient-oriented research, and mentoring of clinical investigators. Description of Patient-Oriented Research: The goals of Dr. Shuldiner's patient-oriented research program is to identify genes for type 2 diabetes, obesity and insulin resistance, and to define the clinical/pathophysiological, cellular and molecular mechanisms whereby these gene variants increase susceptibility to these disorders. Although Dr. Shuldiner is conducting several patient-oriented research projects toward these goals, this proposal described Dr. Shuldiner's main ongoing protocol: Genetics of Diabetes in the Old Order Amish. This is a large study of 1076 Amish subjects from a single 11 generation pedigree that weds clinical research and state-of-the-art molecular genetic approaches to identify obesity and type 2 diabetes susceptibility loci (and ultimately genes). One of the strengths of Dr. Shuldiner's research program is that he applies both clinical and molecular/genetic approaches in a seamless bench to bedside program. Termed "Molecular Medicine", this approach is a prelude to patient-oriented research of the 21st century. Significance: It is likely that the elucidation of genetic variants that predispose to common disease like type 2 diabetes and obesity will provide critical insights into underlying molecular mechanisms which will lead to new molecular targets for the design of novel and effective therapeutic agents. Furthermore, these studies will lead to clinical tests that will be useful at the bedside to determine an individual's genetic burden of disease susceptibility genes so that preventive strategies can be instituted. Training of tomorrow's patient-oriented researchers in Molecular Medicine will allow researchers to harness advances in molecular biology and genetics and apply them in new and innovative ways to clinical researchers, and at the bedside.